Gender Differences
Takotsubo syndrome predominantly affects post-menopausal women. In the German Takotsubo syndrome registry (324 patients; 91 % female and 9 % male with a mean age of 68 ± 12 versus 66 ± 12 years, respectively), both genders showed similar demographic and clinical characteristics.8 Emotional stress or no identifiable trigger were more prevalent in triggering episodes in women. Conversely a physical stress-triggering event, shock and/or resuscitation on presentation and higher levels of cardiac biomarkers (troponin), QT prolongation were more frequent in men.
The National Inpatient Sample USA cohort (2008–2009; 24,701 Takotsubo syndrome patients) reports significantly higher mortality rates in male (8.4 % male versus 3.6 % females; p<0.0001), perhaps reflecting the higher frequency of underlying severe critical illness and secondary Takotsubo syndrome (36.6 % in men versus 26.8 % in women; p< 0.0001).30
Age
Elderly patients are at higher risk of Takotsubo syndrome and related major complications, whereas fewer than 10 % of patients are below 50 years of age.29,31 In the Takotsubo Italian Network, Takotsubo syndrome patients older than 65 years have greater prevalence of hypertension, cerebrovascular disease, a lower glomerular filtration rate and LVEF at discharge. Older adults (≥75 years) have higher in-hospital complications and in-hospital mortality rates (6.3 % versus 2.8 % of overall in-hospital mortality).9
Pathophysiology
Given the frequently sudden, unexpected stressful precipitant, the signs of sympathetic activation at presentation and the secondary medical triggers that also lead to extreme sympathetic activation, the role of catecholamines appears central to the pathophysiology of Takotsubo cardiomyopathy. Serum catecholamine levels at presentation are significantly elevated compared with both resting levels in the individual patient and to levels in comparable patients with acute heart failure secondary to acute myocardial infarction.32 Several varieties of iatrogenic Takotsubo syndrome cases have been reported after administration of sympathomimetic drugs; for example, dobutamine in stress echocardiography.33
Several hypotheses have been proposed to explain the unique cardiac appearance in Takotsubo syndrome and the cardiac response to severe stress. These can be broadly divided into vascular and myocardial causes.
Acute Multivessel Coronary Spasm
The initial cases described in Japan frequently had concomitant vasospasm at diagnostic coronary angiography and it is conceivable that some individuals may be prone to multivessel coronary artery spasm. Some authors propose that Takotsubo syndrome results from multivessel vasospasm and is a form of ischaemic stunning with superimposed catecholamines.34 In some cases vasospasm correlates with the region of dysfunction, but equally in other cases it does not, which goes against vasospasm as the cause of Takotsubo syndrome.35 There are also significant differences in histopathological features when examining endomyocardial biopsies taken from patients with Takotsubo syndrome that show a pattern of myocardial abnormalities not associated with infarcted, stunned or hibernating myocardium, which would not support a primary vascular cause.36 All patients showed the typical contractile pattern of Takotsubo and complete functional recovery within 12 ± 3 days. In ‘acute’ biopsies, many vacuoles of different sizes were found with intracellular accumulation of glycogen. Structural deteriorations characterised by disorganisation of contractile and cytoskeletal proteins could be seen, but evidence of oncotic and apoptotic cell death, as well as infarction, were absent.
Acute Left Ventricular Outflow Tract Obstruction
Acute LV outflow tract obstruction (LVOTO) has been proposed as the cause for Takotsubo syndrome. Individuals may develop a dynamic mid- cavity LV obstruction under catecholamine excess. Potentially older women with smaller hearts, who frequently have prominent septal bulges, could be predisposed to acute LVOTO during intense stress and sympathetic activation. This could explain the transient nature of the regional dysfunction as the apical wall stress would subsequently be reduced by the ensuing ischaemia and apical dysfunction, limiting pressure necrosis and infarction. LVOTO was noted in 25 % of cases in the acute phase of Takotsubo syndrome,37 which indicates that it can be a contributory factor in a subset of patients but is unlikely to be the underlying main cause of Takotsubo syndrome.